A complex interplay of positive and negative signals regulates T cell activation and maintenance of T cell effector function. Members of the TNF ligand/TNF receptor superfamily figure prominently in this matrix of signals, bridging cells of the immune system, as well as with cells of other organ systems. In so doing, TNF superfamily members contribute to both tissue homeostasis and pathogenesis, via effects on cell survival and death, cellular differentiation, and inflammation. From the standpoint of autoimmune pathogenesis, interesting members of the TNF ligand superfamily are TNF-related apoptosis-inducing ligand (TRAIL) and OX40 ligand.
TRAIL binds to a number of different cognate receptors of the TNF receptor superfamily, some leading to triggering of intracellular signaling pathways and others simply acting as decoy receptors. The triggering receptors in humans are TRAIL-R1, TRAIL-R2, and osteoprotegrin, and in mice the sole triggering receptor is DR5. Virtually all cells of the immune system (T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, monocytes, granulocytes) upregulate surface TRAIL and/or release soluble TRAIL stored in secretory vesicles in response to interferon and other activation signals. TRAIL inhibits autoimmunity in several animal models. Evidence for TRAIL's capacity to inhibit experimental autoimmune encephalitis (EAE), a murine model for multiple sclerosis (MS), has come from experiments invoking TRAIL−/− knockout mice, soluble TRAIL receptor (sDR5) or neutralizing anti-TRAIL mAb capable of blocking TRAIL function, and embryonic stem cell-derived dendritic cells co-expressing TRAIL and pathogenic MOG (myelin oligo-dendrocyte glycoprotein peptide). Interestingly, in MS patients, soluble TRAIL has emerged as a response marker for IFN-β therapy, with those most likely to respond to treatment showing early and sustained soluble TRAIL induction after therapy. Yet, TRAIL's impact on MS/EAE may be more complex, for example, the suggestion that TRAIL may promote brain cell apoptosis. Both TRAIL and FasL have been implicated in inhibition of T cells and the induction of apoptosis in T cells.
CD134, also known as the OX40 receptor, is a member of the TNF receptor superfamily, and is found predominantly on activated T-cells (Lamb et al., 1999 Cytometry 38: 238-243), while its ligand, OX40L (also a member of the TNF superfamily), is expressed on activated B-cells, dendritic cells and endothelial cells. OX40L:OX40 signaling is also associated with effector memory cell survival and function (Gramaglia et al., 2000 J Immunol 165: 3043-3050); (Soroosh et al., 2006 J Immunol 176: 5975-5987); (Soroosh et al., 2007 J Immunol 179: 5014-5023).
Multiple sclerosis is a debilitating neurological disease, and despite an expanding set of treatment options, there remains a pressing need for more effective therapeutic agents. While the precise etiology of MS is unknown, key features of its pathogenesis and clinical evolution are emerging. Pathogenic effector T cells are thought to be pivotal in driving the disease, and thus many therapeutic paths are converging on these cells, with goals such as blocking their activation and re-activation, eliminating them from the larger T cell reservoir, and interfering with their transit to sites of pathogenesis within the CNS.
Localized gene therapy in autoimmune demyelinating disease of the central nervous system (CNS) has evolved greatly over the years. Local immunogene therapy in MS and EAE has become a viable option since the lesions in these diseases are spread all over the CNS. Compared to the systemic delivery route, administering immunogenes locally into the CNS has been more efficacious. Injecting naked DNA after incorporation into cationic lipid leads to transient expression. Use of replication deficient viral vectors such as adeno viral or HSV vectors has led to reliable expression of the protein and successful treatment of EAE. Gene transfer has thus become a viable option, particularly when localized expression of immunogenes is desirable, such as in joints, the CNS, and other body spaces/compartments.
What is needed are fusion proteins that provide the constellation of activities associated with each of these important signaling axes, for use in the treatment of autoimmune diseases, including multiple sclerosis, for both systemic and localized administration.